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Compositions and Methods for the Treatment of Diseases Associated with Aberrant Cilia Assembly and Regulation

a technology of aberrant cilia and cilia, applied in the field of molecular biology and ciliaassociated structural and cellular signal transduction, can solve the problems of cancer promotion by defective ciliary signaling

Inactive Publication Date: 2010-06-03
FOX CHASE CANCER CENTER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods for identifying agents that can modulate the function and assembly / disassembly of cilia, which are important for kidney health. One method involves incubating cells with a test agent and assessing any changes in ciliary function. Another method involves creating a mouse model for assessing the effect of a test agent on kidney cyst formation. The invention also provides a method for identifying agents that can disrupt the formation of a calmodulin-Aurora A complex, which is involved in polycystic kidney disease. Finally, the invention provides a method for inhibiting the progression of polycystic kidney disease in patients by administering an aurora kinase inhibitor.

Problems solved by technology

The frequent deregulation of these pathways during cell transformation, together with the common disappearance of cilia in transformed cells, raises the possibility that defective ciliary signaling may promote cancer.

Method used

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  • Compositions and Methods for the Treatment of Diseases Associated with Aberrant Cilia Assembly and Regulation
  • Compositions and Methods for the Treatment of Diseases Associated with Aberrant Cilia Assembly and Regulation
  • Compositions and Methods for the Treatment of Diseases Associated with Aberrant Cilia Assembly and Regulation

Examples

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example i

[0054]We demonstrate that an association between AurA and HEF1 at cilia in response to extracellular cues is required for ciliary disassembly. We also show that AurA activation is independently sufficient to induce rapid ciliary resorption, and that AurA acts in this process through phosphorylating HDAC6, thus stimulating HDAC6-dependent tubulin deacetylation (Hubbert et al., 2002) and destabilizing the ciliary axoneme. Importantly, our identification of a spatiotemporally restricted action of AurA at the ciliary basal body in cells emerging from G0 demonstrates an unexpected non-mitotic activity for AurA in vertebrate cells. We also determine that small molecule inhibitors of AurA and HDAC6 reduce regulated disassembly of cilia, which may have important implications for the action of these drugs in the clinic. Together, these data reveal important activities for HEF1, AurA, and HDAC6 in regulation of ciliary resorption, which should also inform the actions of these proteins in cell...

example 2

Generation of a Mouse Model to Study PKD

[0071]At present, there are numerous competing models to explain the basis for cyst formation, and the differences between the various syndromes associated with kidney cysts. Studies of the signaling changes that occur in PKD have identified anomalous function of pathways that affect proliferation, cell cycle, and apoptosis (Edelstein, C. L. (2005) Cell Cycle 4:1550-4). Downstream elements of these signaling pathways include the tumor suppressors PTEN, TSC2, and p53, the oncogenes Bcl-2 and Akt, and other important growth regulators such as mTOR (Shillingford, J. M. et al. (2006) PNAS 103: 5466-71). Current therapeutic strategies are attempting to exploit this information by using drugs that target the relevant processes and pathways, such as the use of caspase inhibitors to reduce apoptosis, and mTOR inhibitors to block cell proliferation (Tao Y., et al. (2005) PNAS 102: 6954-9). In some cases, these approaches are alleviating symptoms and sl...

example 3

REFERENCES FOR EXAMPLE 3

[0153]Anand, S., Penrhyn-Lowe, S., and Venkitaraman, A. R. (2003). AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 3, 51-62.[0154]Andrews, P. D. (2005). Aurora kinases: shining lights on the therapeutic horizon? Oncogene 24, 5005-5015.[0155]Anyatonwu, G. I., Estrada, M., Tian, X., Somlo, S., and Ehrlich, B. E. (2007). Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc Natl Acad Sci USA 104, 6454-6459.[0156]Battini, L., Macip, S., Fedorova, E., Dikman, S., Somlo, S., Montagna, C., and Gusella, G. L. (2008). Loss of polycystin-1 causes centrosome amplification and genomic instability. Hum Mol Genet. 17, 2819-2833.[0157]Benzing, T., and Walz, G. (2006). Cilium-generated signaling: a cellular GPS? Curr Opin Nephrol Hypertens 15, 245-249.[0158]Bischoff, J. R., Anderson, L., Zhu, Y., Mossie, K., Ng, L., Souza, B., Schryver, B., Flanagan, P., Clairvoyant, F., Ginther,...

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Abstract

Compositions and methods are provided for identifying agents which have efficacy for the treatment of disorders related to aberrant cilial structure and function, including polycystic kidney disease.

Description

[0001]This application is a Continuation-in-Part Application of U.S. patent application Ser. No. 12 / 374,209 filed Apr. 2, 2009, which is a §371 Application of PCT / US07 / 73722, filed Jul. 17, 2007, which claims priority to U.S. Provisional Applications 60 / 831,479 and 60 / 925,272 filed Jul. 17, 2006 and Apr. 19, 2007. This CIP application also claims priority to U.S. Provisional Application, 61 / 122,303 filed Dec. 12, 2008. The entire disclosures of each of the foregoing application are incorporated herein by reference.[0002]Pursuant to 35 U.S.C. §202(c), it is acknowledged that the U.S. Government has certain rights in the invention described, which was made in part with funds from the National Institutes of Health, Grant Numbers RO1 CA63366, CA-06927, DOD W81XWH-07-1-0676 and RO1 CA-113342.FIELD OF THE INVENTION[0003]The present invention relates to the fields of molecular biology and cilia-associated structural and cellular signal transduction. More specifically, the invention provide...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7088C12Q1/48A61P13/12C12Q1/68
CPCA61K31/7088C12N15/113C12N15/1137C12N2310/14G01N33/5008G01N2333/91215A61P13/12
Inventor PLOTNIKOVA, OLGA V.PUGACHEVA, ELENA N.GOLEMIS, ERICA A.
Owner FOX CHASE CANCER CENTER
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